1. 2011 Organ Donation Congress Buenos Aires, November 27-30, 2011 Graft and Patient Outcomes Challenges in Liver Transplantation Federico G. Villamil Liver Transplantation Unit Buenos Aires British Hospital

5. Challenges in Liver Transplantation Hepatitis B

6. OLT for Hepatitis B : “A happy story” HBV Recurrence 1980’s No inmunoprofilaxis 80-90% HBIg monotherapy 20-30% HBIg + LAM 5-10% HBIg + ADV (  LAM) 2-5% HBIg +ETV o TDF ?? From an absolute contraindication to a universally accepted indication 1990 2000 2005 2010 HBIg-free prophylaxis?

7. Challenges in Liver Transplantation Hepatitis C

9. Effect of Donor Age on Severity of HCV Recurrence Following OLT Berenguer et al (2002) % HCV-related graft cirrhosis Donor Age

10. Is CsA antiviral in vivo? Are mTor inhibitors anti-fibrogenic? Immunosuppression in Hepatitis C Changes in immunosuppresion over time should be slow and gentle  Avoid intense imunosuppression followed by rapid withdrawal For mild episodes of rejection intensification of baseline immunosuppression should be attempted before administering steroid boluses

11. The HCV- Diabetes -Kidney Connection HCV Diabetes (IR) Renal failure HCV is an Independent predictor of renal failure and may accelerate the progression of diabetic nephropathy HCV increases the risk of DM Diabetes (IR) increases the severity of HCV

13. Histological Outcome of Patients With SVR Post-OLT Inflammation Fibrosis %

14. Antiviral Therapy Improves Long-Term Outcome of HCV Recurrence * Significant differences SVR NR Treated Untreated 100%* 93%* NA 43% 69% NA NA 74%* 92.5%* NA 30 Kornberg (08) 62% 89 Berenguer (08) 66% 165 Veldt (08) Patient Survival (5-7 Years) N Author

15. Efficacy of PEG-Ribavirin Therapy for HCV Recurrence 25 reported studies including 835 patients 8% 55% SVR (all genotypes): 259/835 (31%)

16. There is an urgent need for more safe and effective antiviral agents SVR in Naive Genotype 1 Patients Triple therapy Triple therapy Telaprevir Boceprevir %

17. Garg V et al. Hepatology 2011 AUC increase x 70 Tacrolimus + telaprevir Tacrolimus Impact of Telaprevir on CNI Exposure

18. Hepatocellular Carcinoma Challenges in Liver Transplantation

19. Liver Transplantation for HCC Mazzaferro V y col (1996) Imaging studies with a single nodule <5 cm or up to 3 nodules <3 cm Recurrence-free survival 90% 86% 83% 83% HCC recurrence: 8% % “ Milan Criteria”

21. Is tumor biology the answer? Can we safely go beyond Milan Criteria?

22. Results of OLT in HCC and non-HCC Patients According to Immunosuppression Toso C et al NS 78% 79% NS 70% 68% MMF <0.001 79% 73% NS 69% 69% CsA <0.001 73% 79% NS 68% 70% Tac NS 78% 79% <0.01 68% 74% Anti-CD25 NS 79% 74% <0.05 69% 83% Sirolimus p No Yes p No Yes No HCC (n=12167) HCC (n=2491) 5-Year Survival Droga “ Anti-cáncer agent”

23. 5-Year survival Toso C et al (2010) Results of OLT in HCC Patients According to Immunosuppression Multivariate Analysis (HCC patients) Sirolimus: HR 0.53 (0.31-0.92) p<0.05 Anti-CD25: HR 0.64 (0.45-0.9) p<0.01

25. Challenges in Liver Transplantation NASH

26. Metabolic Syndrome and Liver Transplantation Metabolic syndrome in up to 60% of post-transplant patients 30-40% 20-75% DM or IGT 60-70% 67% Hypertension 50-70% 12-85% Elevated lipids OLT NAFLD

27. Present and Future Demand for Liver Transplantation for NASH % of LT Charlton MR, Clin Gastro & Hep 3:2005.

30. Actuarial Rates of Fibrosis in Patients with HCV Recurrence Fundación Favaloro 1995-2007 72 consecutive HCV+ patients with mean follow-up of 69 months and 5  2 protocol biopsies 97% 81% 49% 21% F1 F2 F3 F4

31. HCV Infection is Associated with Decreased Post-OLT Survival HCV-Neg (n=6597) HCV-Pos (n=4439) 81.8% 76.6% 77.8 69.9 p<0.0001 HCV recurrence is the major cause of graft loss and death Forman L et al (2002)

33. Tumor Size is a Surrogate Marker for Histological Predictorsof Recurrence Figueras J et al (2001) Tumor diameter of main nodule (n=305) %